ClinVar Miner

Submissions for variant NM_000329.3(RPE65):c.361dup (p.Ser121fs)

dbSNP: rs121918844
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Leber Congenital Amaurosis/early Onset Retinal Dystrophy Variant Curation Expert Panel, ClinGen RCV003768021 SCV004697404 pathogenic RPE65-related recessive retinopathy 2024-02-20 reviewed by expert panel curation The NM_000329.3(RPE65):c.361dup (p.Ser121fs) frameshift variant introduces a premature stop codon in exon 5 of 14 and is predicted to trigger nonsense-mediated decay (PVS1). It is reported in the literature in a compound heterozygous state in at least one proband (by whole exome sequencing) who was diagnosed with Leber congenital amaurosis and exhibits infantile onset (1 pt), reduced visual acuity (1 pt), nyctalopia (required, 0.5 pts), light gazing (1 pt), nystagmus (1 pt), RPE mottling (0.5 pt), attenuated retinal vessels (0.5 pt), flat rod ERG (required, 1 pt), and flat cone ERG (1 pt), which together is highly specific for RPE65-related recessive retinopathy (PMID: 30870047, PP4_Moderate). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: PVS1, PP4_Moderate, and PM2_Supporting. (VCEP specifications version 1.0.0; date of approval 09/21/2023)
Cytogenetics and Genomics Laboratory, Medical University of South Carolina RCV000754975 SCV000803385 pathogenic Leber congenital amaurosis 2018-06-01 criteria provided, single submitter research
Labcorp Genetics (formerly Invitae), Labcorp RCV001387317 SCV001587918 pathogenic Leber congenital amaurosis 2; Retinitis pigmentosa 20 2018-05-10 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in RPE65 are known to be pathogenic (PMID: 9326941, 9501220). This variant has been observed in an individual affected with Leber's congenital amaurosis (PMID: 24066033). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Ser121Phefs*10) in the RPE65 gene. It is expected to result in an absent or disrupted protein product.
Baylor Genetics RCV003465542 SCV004209264 pathogenic Leber congenital amaurosis 2 2023-06-13 criteria provided, single submitter clinical testing

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